Sequelae of large-head metal-on-metal hip arthroplasties: Current status and future prospects.
Large-head metal-on-metal (MoM) bearings were re-popularised in the late 1990s with the introduction of modern hip resurfacing (HR), followed closely by large metal head total hip arthroplasty (THA). A worldwide increase in the use of MoM hip arthroplasty subsequently saw a sharp decline, due to serious complications.MoM was rapidly adopted in the early 2000s until medical device alerts were issued by government regulatory agencies and national and international organisations, leading to post-marketing surveillance and discontinuation of these implants.Guidelines for MoM hip implant follow-up differ considerably between regulatory authorities worldwide; this can in part be attributed to missing or conflicting evidence.The authors consider that the use of large-head MoM THA should be discontinued. MoM HR should be approached with caution and, when considered, should be used only in patients who meet all of the recommended selection criteria, which limits its indications considerably.The phased introduction of new prostheses should be mandatory in future. Close monitoring of outcomes and long-term follow-up is also necessary for the introduction of new prostheses. Cite this article: van Lingen CP, Zagra LM, Ettema HB, Verheyen CC. Sequelae of large-head metal-on-metal hip arthroplasties: current status and future prospects. EFORT Open Rev 2016;1:345-353. DOI: 10.1302/2058-5241.1.160014.


Fibrin sealant in punch hair grafting.
In this study it was shown that fibrin sealant used in eight consecutive patients undergoing their first session of punch hair grafting after sagittal midline excision(s) reduces the hair survival rate by about 2 hairs per graft from 21.74 on the non-glued side to 19.79 on the glued side (p less than 0.01). The authors did not find this sealant beneficial in routine punch hair transplantation but found it to be of some potential value if the grafts are to be left without any dressing immediately postoperatively.


Simultaneous brain, brainstem, and spinal cord pharmacological-fMRI reveals involvement of an endogenous opioid network in attentional analgesia.
Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) - rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.


Distraction osteogenesis (callotasis) for pelvic closure in bladder exstrophy.
The success of urogenital reconstruction in bladder exstrophy is dependent on how successfully the pelvic ring can be closed. In patients with this disorder, the pubic bones are short and separated. A two-component plate-rod combination was designed to widen the pelvic ring using distraction osteogenesis (callotasis). After a middiagonal iliac osteotomy, two components of the implant are connected with two bolts passing through the iliac bone. After 10 days, the rods outside the skin are approximated gradually. When the pubic bones get close, they are fixed by heavy nonabsorbable sutures. The current study included 14 patients who were operated on between 1990 and 1996. The mean followup was 6 years. No neurologic or vascular complications developed. Successful tension-free closure of the abdominal wall was achieved in all but one patient. Urogenital reconstruction was done in the second stage. In all but one patient, the bladder was closed in one stage of urogenital reconstruction. In one patient (7%), a deep infection developed for which the patient needed early implant removal resulting in failure of the urogenital reconstruction. The described method addresses the pathoanatomy of the pelvic ring. The diameter of the pelvic ring can be widened and the pubic bones can be approximated without a significant increase in tension.


Androstadienone odor thresholds in adolescents.
A sex-related difference in olfactory sensitivity to androstenone has been reported to occur during adolescence. More males than females exhibited anosmia to androstenone, or an increase in androstenone threshold with age. The current study addressed the question whether similar, sexually dimorphic effects of aging over puberty can also be found for androstadienone. A total of 102 subjects participated (36 females, 66 males). Similar to previous investigations, subjects were divided into a group of 47 individuals with a mean age of 13.3 years, defined as pre/peri-pubertal, and a group of 55 subjects with a mean age of 17.1 years, defined as post-pubertal. All subjects underwent tests for verbal abilities, general olfactory function, and measurements of androstadienone thresholds. The study provided the following major results: (1) Male subjects exhibited higher androstadienone sensitivity in the pre/peri-pubertal group as compared to the post-pubertal group. This difference was not observed in female subjects. Correspondingly, a negative correlation between age and androstadienone sensitivity was found for male subjects, but not for female subjects. (2) In contrast to this sex-specific change of the androstadienone odor threshold, verbal skills and odor identification abilities increased with age in all subjects regardless of their sex. In conclusion, the present observations confirm previous research on sex-differentiated effects of aging during puberty on sensitivity towards odorous steroids. While the underlying causes are unknown, it may be hypothesized that the decreased sensitivity could result from the increased endogenous levels of androstadienone in male subjects. Future studies should include both steroid and non-steroid odorants to further explore these age-related changes.


Your Path to Transplant: A randomized controlled trial of a tailored expert system intervention to increase knowledge, attitudes, and pursuit of kidney transplant.
Individually tailoring education over time may help more patients, especially racial/ethnic minorities, get waitlisted and pursue deceased and living donor kidney transplant (DDKT and LDKT, respectively). We enrolled 802 patients pursuing transplant evaluation at the University of California, Los Angeles Transplant Program into a randomized education trial. We compared the effectiveness of Your Path to Transplant (YPT), an individually tailored coaching and education program delivered at 4 time points, with standard of care (SOC) education on improving readiness to pursue DDKT and LDKT, transplant knowledge, taking 15 small transplant-related actions, and pursuing transplant (waitlisting or LDKT rates) over 8 months. Survey outcomes were collected prior to evaluation and at 4 and 8 months. Time to waitlisting or LDKT was assessed with at least 18 months of follow-up. At 8 months, compared to SOC, the YPT group demonstrated increased LDKT readiness (47% vs 33%, P = .003) and transplant knowledge (effect size [ES] = 0.41, P < .001). Transplant pursuit was higher in the YPT group (hazard ratio: 1.44, 95% confidence interval: 1.15-1.79, P = .002). A focused, coordinated education effort can improve transplant-seeking behaviors and waitlisting rates. ClinicalTrials.gov registration: NCT02181114.


J. Leonard Goldner Award 2011: changes in pain, function, and gait mechanics two years following total ankle arthroplasty performed with two modern fixed-bearing prostheses.
Total ankle replacement (TAR) continues to grow as an alternative to arthrodesis for patients who suffer from end-stage ankle arthritis. The purpose of this study was to examine changes in gait mechanics from before surgery to 1 and 2 years after surgery in patients who received a fixed-bearing TAR. Fifty-one patients with a primary fixed-bearing TAR and no complications requiring further surgery were identified from a database and enrolled in this non-randomized study. Subjects were examined preoperatively, and at 1 and 2 years postoperatively. Three-dimensional joint mechanics and ground reaction forces (GRF) were collected during level walking. The Four Square Step Test, Timed Up and Go (TUG), VAS, and the AOFAS-Hindfoot score were assessed for each subject at each time point. TUG, VAS and AOFAS-Hindfoot score along with all measured kinetic parameters demonstrated significant improvements across all of the time points (p < 0.05). Four Square Step Test time was significantly improved between the preoperative and 2-year postoperative time point (p < 0.05). Measured ankle dorsiflexion angles did not demonstrate significant change between any time points. All of the observed changes suggest improved or maintained functioning in patients who received a TAR with the greatest improvement occurring within the first year. Sagittal plane ankle range of motion and dorsiflexion angle at heel strike were unchanged across all of the time points. The results of this study indicate that patients with end-stage osteoarthritis demonstrate improvements in pain and gait up to 2 years following surgery while maintaining ankle range of motion.


Switchgrass genomic diversity, ploidy, and evolution: novel insights from a network-based SNP discovery protocol.
Switchgrass (Panicum virgatum L.) is a perennial grass that has been designated as an herbaceous model biofuel crop for the United States of America. To facilitate accelerated breeding programs of switchgrass, we developed both an association panel and linkage populations for genome-wide association study (GWAS) and genomic selection (GS). All of the 840 individuals were then genotyped using genotyping by sequencing (GBS), generating 350 GB of sequence in total. As a highly heterozygous polyploid (tetraploid and octoploid) species lacking a reference genome, switchgrass is highly intractable with earlier methodologies of single nucleotide polymorphism (SNP) discovery. To access the genetic diversity of species like switchgrass, we developed a SNP discovery pipeline based on a network approach called the Universal Network-Enabled Analysis Kit (UNEAK). Complexities that hinder single nucleotide polymorphism discovery, such as repeats, paralogs, and sequencing errors, are easily resolved with UNEAK. Here, 1.2 million putative SNPs were discovered in a diverse collection of primarily upland, northern-adapted switchgrass populations. Further analysis of this data set revealed the fundamentally diploid nature of tetraploid switchgrass. Taking advantage of the high conservation of genome structure between switchgrass and foxtail millet (Setaria italica (L.) P. Beauv.), two parent-specific, synteny-based, ultra high-density linkage maps containing a total of 88,217 SNPs were constructed. Also, our results showed clear patterns of isolation-by-distance and isolation-by-ploidy in natural populations of switchgrass. Phylogenetic analysis supported a general south-to-north migration path of switchgrass. In addition, this analysis suggested that upland tetraploid arose from upland octoploid. All together, this study provides unparalleled insights into the diversity, genomic complexity, population structure, phylogeny, phylogeography, ploidy, and evolutionary dynamics of switchgrass.


Prevalence and severity of oral disease in adults with chronic kidney disease: a systematic review of observational studies.
Oral disease may be increased in people with chronic kidney disease (CKD) and, due to associations with inflammation and malnutrition, represents a potential modifiable risk factor for cardiovascular disease and mortality. We summarized the prevalence of oral disease in adults with CKD and explored any association between oral disease and mortality. We used systematic review of observational studies evaluating oral health in adults with CKD identified in MEDLINE (through September 2012) without language restriction. We summarized prevalence and associations with all-cause and cardiovascular mortality using random-effects meta-analysis. We explored for sources of heterogeneity between studies using meta-regression. Eighty-eight studies in 125 populations comprising 11 340 adults were eligible. Edentulism affected one in five adults with CKD Stage 5D (dialysis) {20.6% [95% confidence interval (CI), 16.4-25.6]}. Periodontitis was more common in CKD Stage 5D [56.8% (CI, 39.3-72.8)] than less severe CKD [31.6% (CI, 19.0-47.6)], although data linking periodontitis with premature death were scant. One-quarter of patients with CKD Stage 5D reported never brushing their teeth [25.6% (CI, 10.2-51.1)] and a minority used dental floss [11.4% (CI, 6.2-19.8)]; oral pain was reported by one-sixth [18.7% (CI, 8.8-35.4)], while half of patients experienced a dry mouth [48.4% (CI, 37.5-59.5)]. Data for kidney transplant recipients and CKD Stages 1-5 were limited. Oral disease is common in adults with CKD, potentially reflects low use of preventative dental services, and may be an important determinant of health in this clinical setting.


The cost-effectiveness and budget impact of intravenous versus oral proton pump inhibitors in peptic ulcer hemorrhage.
The most cost-effective route of administering proton pump inhibitor (PPI) therapy in peptic ulcer hemorrhage remains uncertain. Oral (PO) PPI therapy may be less effective than intravenous (IV) PPI therapy, but is less expensive and does not mandate a 72-hour posthemostasis hospital stay to complete a full therapeutic course. Because there are currently no published head-to-head clinical trials comparing IV vs PO PPIs, we used decision analysis with budget impact modeling to measure the clinical and economic outcomes of these competing modes of administration. We compared 3 postendoscopic strategies for high-risk peptic ulcer hemorrhage: (1) PO PPI therapy, (2) IV PPI therapy, and (3) IV histamine(2) receptor antagonist therapy. The primary outcomes were cost per quality-adjusted life-year gained, and per-member per-month cost in a hypothetical managed care organization with 1,000,000 covered lives. Compared with the PPI strategies, the histamine(2) receptor antagonist strategy was more expensive and less effective. Of the 2 PPI strategies, using IV instead of PO PPI cost an incremental 708,735 US dollars per year to gain 1 additional quality-adjusted life-year. Substituting IV in lieu of PO PPI cost each member 2.86 US dollars per month to subsidize. The IV PPI strategy became dominant when the rebleed rate with PO PPIs exceeded 24% (base case = 13%), and when the hospital stay on IV PPIs decreased to less than 72 hours. The higher effectiveness of IV PPI therapy may not offset its increased costs vs PO PPI therapy in ulcer hemorrhage. The managed care budget impact of IV PPIs exceeds most benchmarks.


Presence of cytochrome b-245 in NADPH oxidase preparations from human neutrophils.
The composition of NADPH oxidase purified by Red Sepharose chromatography of extracts from human neutrophil membranes was investigated. In contrast to that was recently reported by others, the enzyme isolated according to this procedure contained a high concentration of cytochrome b-245 and little FAD. The results reinforce the belief that cytochrome b-245 is a major component of the NADPH oxidase and plays a fundamental role in the formation of O2-by neutrophils.


Foxp3 expression in macrophages associated with RENCA tumors in mice.
The transcription factor Foxp3 represents the most specific functional marker of CD4+ regulatory T cells (TRegs). However, previous reports have described Foxp3 expression in other cell types including some subsets of macrophages, although there are conflicting reports and Foxp3 expression in cells other than Treg is not well characterized. We performed detailed investigations into Foxp3 expression in macrophages in the normal tissue and tumor settings. We detected Foxp3 protein in macrophages infiltrating mouse renal cancer tumors injected subcutaneously or in the kidney. Expression was demonstrated using flow cytometry and Western blot with two individual monoclonal antibodies. Further analyses confirmed Foxp3 expression in macrophages by RT PCR, and studies using ribonucleic acid-sequencing (RNAseq) demonstrated a previously unknown Foxp3 messenger (m)RNA transcript in tumor-associated macrophages. In addition, depletion of Foxp3+ cells using diphtheria toxin in Foxp3DTR mice reduced the frequency of type-2 macrophages (M2) in kidney tumors. Collectively, these results indicate that tumor-associated macrophages could express Foxp3.


Toll-like receptors, cytokines and the immunotherapeutics of asthma.
Asthma is a complex disease caused by a poorly characterized set of genetic and environmental factors whose pathology is a result of immune dysregulation. Toll-like receptors are pathogen associated molecular pattern receptors expressed by many airway and pulmonary tissues as well as cells of the innate and adaptive immune system. Ligation of toll-like receptors can lead to a change in the expression levels of multiple inflammatory and anti-inflammatory mediators which are involved in the pathogenesis of asthma. These ligands and their receptors are therefore prime candidates in the search for immunotherapeutic treatments of asthma. The use of murine models of allergic asthma as tools for the genetic dissection of this disease should allow the molecular mechanisms underlying asthma to be identified and possibly used as further immunotherapeutic targets.


Head injury and hemorrhagic shock: studies of the blood brain barrier and intracranial pressure after resuscitation with normal saline solution, 3% saline solution, and dextran-40.
The effect of fluid resuscitation from hemorrhagic shock on cerebral edema, intracranial pressure (ICP), and blood brain barrier function was investigated in the presence of a simulated head injury. Beagle dogs were anesthetized and ICP was measured via a right subarachnoid bolt while a contralateral epidural balloon was inflated in the left hemicranium to mimic a closed head injury. Forty percent of the dogs' blood was shed and the shock state was maintained for 1 hour. Resuscitation was initiated with shed blood and a volume of either normal saline solution (NS, n = 5), 10% dextran-40 (D-40, n = 6), or hypertonic (3%) saline solution (HS, n = 6) equal to the amount of shed blood. Evans blue solution was infused intravenously, and intravascular volume was then maintained with normal saline solution. Control (n = 5) dogs did not undergo shock, but received equivalent volumes of normal saline solution and Evans blue solution. The dogs were killed after 2 hours of resuscitation, and the brains were removed, weighed, and fixed in formalin. The average intracranial pressure value after epidural balloon inflation was 18.6 +/- 0.80 mm Hg and decreased equally in all groups during the shock period, averaging 10.8 +/- 1.24 mm Hg at the end of the shock period. Fluid resuscitation markedly elevated ICP in the NS and D-40 groups, reaching maximal values of 46.6 +/- 12.11 mm Hg and 45.3 +/- 28.95 mm Hg, respectively. Maximal ICP values in control and HS groups measured 21.8 +/- 1.36 mm Hg and 15.8 +/- 2.04 mm Hg, respectively (p less than 0.25 for HS versus NS control). Wet brain weights were significantly less in the HS group compared with either NS or D-40 groups (p less than 0.05). Coronal sections of fixed HS brains showed deep cortical Evans blue staining on the side of balloon injury. Therefore, in the presence of an intracranial mass lesion, resuscitation with hypertonic (3%) saline solution is accompanied by lower ICP values and less cerebral edema than is isotonic saline or colloid resuscitation. Blood brain barrier function is not restored by hypertonic saline solution resuscitation.


Number of infection events per cell during HIV-1 cell-free infection.
HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.


Anaphylaxis in chopped guinea pig lung. II. Enhancement of the anaphylactic release of histamine and slow reacting substance by certain dibasic aliphatic acids and inhibition by monobasic fatty acids.
The quantitative release of histamine and slow reacting substance by specific antigen from perfused, chopped, sensitized guinea pig lung has been used to study the opposing effects of monobasic and certain dibasic fatty acids on the anaphylactic reaction. The anaphylactic release of histamine and slow reacting substance is doubled by the addition of 0.5 mM of succinic or maleic acid to the reaction mixture, and enhancement is definite with as little as 0.05 mM of succinic acid. Prolonged preincubation of the tissue with the dibasic acids is not required, for 60 to 90 per cent of maximal enhancement is apparent when the antigen is added to the tissue only 10 seconds after succinic or maleic acid. The increased histamine release is not due to a qualitative change in the time course of histamine release, is not the result of increased histamine formation, and cannot be attributed to an effect on the tricarboxylic acid cycle. The enhancement seems to be due to potentiation of some step activated by the antigen-antibody interaction and common to both the release of histamine and slow reacting substance. The structural configuration required for a dibasic acid to enhance the anaphylactic reaction in guinea pig lung is quite specific; the carboxyl groups should be separated by a two carbon chain, and must be free or fixed in the cis position. The monobasic fatty acids from valeric to dodecanoic inhibit the anaphylactic release of histamine, and the concentration needed to produce 50 per cent inhibition decreases with increasing chain length. The introduction of a polar group, amino or carboxyl, into the hydrocarbon residue diminishes or abolishes inhibitory capacity. The inhibition produced by the fatty acids is neither due to calcium binding nor due to prevention of effective antigen-antibody interaction; the fatty acids probably inhibit by acting on an antigen-antibody-activated step. The inhibition of the anaphylactic release of histamine and slow reacting substance produced by caproic or decanoic acid can be reversed by the enhancing effect of succinic acid, and vice versa. Thus, compounds normally present in mammalian tissue can greatly influence the intensity of the in vitro anaphylactic reaction in the guinea pig.


Eoscyphella luciurceolata gen. and sp. nov. (Agaricomycetes) Shed Light on Cyphellopsidaceae with a New Lineage of Bioluminescent Fungi.
During nocturnal field expeditions in the Brazilian Atlantic Rainforest, an unexpected bioluminescent fungus with reduced form was found. Based on morphological data, the taxon was first identified as belonging to the cyphelloid genus Maireina, but in our phylogenetic analyses, Maireina was recovered and confirmed as a paraphyletic group related to genera Merismodes and Cyphellopsis. Maireina filipendula, Ma. monacha, and Ma. subsphaerospora are herein transferred to Merismodes. Based upon morphological and molecular characters, the bioluminescent cyphelloid taxon is described as the new genus Eoscyphella, characterized by a vasiform to urceolate basidiomata, subglobose to broadly ellipsoid basidiospores, being pigmented, weakly to densely encrusted external hyphae, regularly bi-spored basidia, unclamped hyphae, and an absence of both conspicuous long external hairs and hymenial cystidia. Phylogenetic analyses based on ITS rDNA and LSU rDNA support the proposal of the new genus and confirm its position in Cyphellopsidaceae. Eoscyphella luciurceolata represents a new lineage of bioluminescent basidiomycetes with reduced forms.


Synthesis and structure-activity relationship studies of N-terminal analogues of the lipopeptide antibiotics brevicidine and laterocidine.
The brevicidine and laterocidine family of lipopeptide antibiotics exhibit strong activity against multidrug-resistant Gram-negative bacteria, while showing low propensity to induce resistance. Both peptides feature a branched lipid tail on the N-terminal residue, which for brevicidine is chiral. Here, we report the synthesis and biological evaluation of a library of brevicidine and laterocidine analogues wherein the N-terminal lipid is replaced with linear achiral fatty acids. Optimal lipid chain lengths were determined and new analogues with strong activity against colistin-resistant E. coli produced.


Chlorine Dioxide is a Better Disinfectant than Sodium Hypochlorite against Multi-Drug Resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii.
In this study, we evaluated and compared the antibacterial activity of chlorine dioxide (ClO2) and sodium hypochlorite (NaClO) on various multidrug-resistant strains in the presence of bovine serum albumin and sheep erythrocytes to mimic the blood contamination that frequently occurs in the clinical setting. The 3 most important species that cause nosocomial infections, i.e., methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa (MDRP), and multidrug-resistant Acinetobacter baumannii (MDRA), were evaluated, with three representative strains of each. At a 10-ppm concentration, ClO2 drastically reduced the number of bacteria of all MDRP and MDRA strains, and 2 out of 3 MRSA strains. However, 10 ppm of NaClO did not significantly kill any of the 9 strains tested in 60 seconds (s). In addition, 100 ppm of ClO2 completely killed all MRSA strains, whereas 100 ppm of NaClO failed to significantly lower the number of 2 MRSA strains and 1 MDRA strain. A time-course experiment demonstrated that, within 15 s, 100 ppm of ClO2, but not 100 ppm of NaClO, completely killed all tested strains. Taken together, these data suggest that ClO2 is more effective than NaClO against MRSA, MDRP, and MDRA, and 100 ppm is an effective concentration against these multidrug-resistant strains, which cause fatal nosocomial infections.


The Effect of DHA Supplementation on Cognition in Patients with Bipolar Disorder: An Exploratory Randomized Control Trial.
Bipolar disorder (BD) is a severe mental disorder with a wide range of cognitive deficits, both in the euthymic and acute phase of the disease. Interestingly, in recent years, there has been a growing interest in investigating the impact of ω-3 polyunsaturated fatty acids on cognition in BD. In this context, the aim of this study is to evaluate the effect of docosahexaenoic acid (C22:6 ω-3, DHA) supplementation on cognitive performances in euthymic BD patients. This is an exploratory, single-centre, double-blind randomized controlled trial evaluating 12 weeks DHA supplementation (1250 mg daily) vs. a placebo (corn oil) in 31 euthymic BD patients compared to 15 healthy controls (HCs) on cognitive functions, assessed by the Brief Assessment of Cognition in Affective Disorder (BAC-A). Plasma levels of DHA were measured. After 12 weeks of treatment, no significant group differences were observed in all neuropsychological tests between the four groups, except for the emotion inhibition test, where HCs with DHA had higher scores compared to either BD with DHA (z = 3.9, p = 0.003) or BD with placebo (t = 3.7, p = 0.005). Although our results showed that DHA could be effective for ameliorating cognition in healthy subjects, future studies are still needed to clarify the impact of DHA on cognition in BD.


Postjunctional alpha-adrenoceptor subtypes in isolated and perfused canine epicardial coronary arteries.
In isolated and perfused canine coronary arteries pretreated with propranolol (5 x 10(-6) M), effects of bunazosin (E 643, a selective alpha 1-antagonist) and DG 5128 (a selective alpha 2-antagonist) on vasoconstrictor responses to phenylephrine, xylazine, clonidine, and norepinephrine (NE) were examined. A stainless steel cannula was inserted into the coronary artery segment (1.1-2.4 mm OD, 1.5 cm long) and perfused with Krebs-Henseleit solution at a constant flow rate. The perfusion pressures were 60-110 mm Hg. Acetylcholine readily caused a vasodilation in used arterial preparations. Phenylephrine produced a strong vasoconstriction in a dose-dependent manner, but xylazine and clonidine induced slight vasoconstrictions and a vasodilation followed by a slight vasoconstriction in large doses. Phenylephrine-induced vasoconstrictions were dose-dependently attenuated by bunazosin but not by DG 5128. Neither bunazosin nor DG 5128 blocked the vascular responses to clonidine and xylazine. NE produced a slight vasoconstriction in the presence of prazosin (10(-6) M), and DG 5128 did not influence that vasoconstriction. Diltiazem significantly suppressed KCl-induced vasoconstriction, but bunazosin did not. Removal of endothelium by 1 mg of saponin significantly attenuated acetylcholine (ACh)-induced vasodilation, but did not suppress clonidine-induced vasodilation. It is suggested that only alpha 1-adrenoceptors are involved in the vasoconstrictions induced by the adrenergic agonists in canine epicardial coronary arteries and that the vascular responses to clonidine and xylazine may be direct actions.


Assessing the distribution of sedimentary C40 carotenoids through time.
A comprehensive marine biomarker record of green and purple sulfur bacteria (GSB and PSB, respectively) is required to test whether anoxygenic photosynthesis represented a greater fraction of marine primary productivity during the Precambrian than the Phanerozoic, as current models of ocean redox evolution suggest. For this purpose, we analyzed marine rock extracts and oils from the Proterozoic to the Paleogene for C40 diagenetic products of carotenoid pigments using new analytical methods. Gas chromatography coupled with tandem mass spectrometry provides a new perspective on the temporal distributions of carotenoid biomarkers for phototrophic sulfur bacteria, specifically okenane, chlorobactane, and paleorenieratane. According to conventional paleoredox interpretations, this revised stratigraphic distribution of the GSB and PSB biomarkers implies that the shallow sunlit surface ocean (<24 m) became sulfidic more frequently in the geologic past than was previously thought. We reexamine whether there is evidence supporting a planktonic source of GSB and PSB pigments in marine systems or whether additional factors are required to explain the marine phototrophic sulfur bacteria record. To date, planktonic GSB and PSB and their pigments have been identified in restricted basins and lakes, but they have yet to be detected in the unrestricted, transiently sulfidic, marine systems. Based on modern observations, additional environmental factors, including basin restriction, microbial mats, or sediment transport, may be required to fully explain GSB and PSB carotenoids in the geologic record.


GRASE (gradient- and spin-echo) MR imaging: a new fast clinical imaging technique.
A novel technique of magnetic resonance (MR) imaging, which combines gradient-echo and spin-echo (GRASE) technique, accomplishes T2-weighted multisection imaging in drastically reduced imaging time, currently 24 times faster than spin-echo imaging. The GRASE technique maintains contrast mechanisms, high spatial resolution, and image quality of spin-echo imaging and is compatible with clinical whole-body MR systems without modification of gradient hardware. Image acquisition time is 18 seconds for 11 multisection body images (2,000/80 [repetition time msec/echo time msec]) and 36 seconds for 22 brain images (4,000/104). With a combination of multiple Hahn spin echoes and short gradient-echo trains, the GRASE technique overcomes several potential problems of echo-planar imaging, including large chemical shift, image distortions, and signal loss from field inhomogeneity. Advantages of GRASE over the RARE (rapid acquisition with relaxation enhancement) technique include faster acquisition times and lower deposition of radio-frequency power in the body. Breath holding during 18-second GRASE imaging of the upper abdomen eliminates respiratory-motion artifacts in T2-weighted images. A major improvement in T2-weighted abdominal imaging is suggested.


Dementia care management in primary care : Current collaborative care models and the case for interprofessional education.
Dementia is one of the most prevalent diseases in the older population. Various dementia care models have been developed to address patient's healthcare needs. They can be described as "collaborative care" or "person-centered care". Referring to the needs of the workforce working with persons with dementia, a key element is the use of interprofessional education (IPE). The purpose of this article is to describe different international collaborative care models to define a minimum standard of healthcare professions for collaborative dementia care in primary care. This helps to identify requirements for IPE to optimize care of people with dementia and to support informal caregivers in the future. In this article six dementia care models from 4 different countries (Germany, USA, UK and Netherlands) are described and compared regarding aims, interventions and healthcare professionals involved. Care teams are minimally comprised of general practitioners or primary care providers, nurses, and social workers. Additional healthcare disciplines may be involved for specific interventions. Mostly, care team members received specific training but such training did not necessarily incorporate the IPE approach. To ensure successful collaboration of professions, IPE training programs should at least consist of the following core topics: (1) early diagnosis, (2) postdiagnostic support, (3) advanced care planning for patients and caregivers and (4) effective collaborative care. The IPE programs for dementia should be expanded and must be widely implemented in order to assess the impact on collaborative practice. This study will provide the knowledge base for structuring IPE trainings developing educational agendas and adapting existing guidelines to improve collaborative dementia care in the future.


[Effect of lumboischialgic scoliosis, kyphosis and hyperlordosis on the functional status of the muscles of the leg].
Simultaneous clinico-electropolymyographic examination of 8 muscles in patients with fixed ischialgic scoliosis, kyphosis, and hyperlordosis has identified several variants of muscular stereotypes in conditions of rest (in the position of free standing), flexing and unflexing. In kyphosis they are characterized by increasing activity of the anterior leg muscles while bending forward and in hyperlordosis, by increasing activity of the posterior muscles of the shin in all kinds of bending.


Glycemic index and disease.
It has been suggested that foods with a high glycemic index are detrimental to health and that healthy people should be told to avoid these foods. This paper takes the position that not enough valid scientific data are available to launch a public health campaign to disseminate such a recommendation. This paper explores the glycemic index and its validity and discusses the effect of postprandial glucose and insulin responses on food intake, obesity, type 1 diabetes, and cardiovascular disease. Presented herein are the reasons why it is premature to recommend that the general population avoid foods with a high glycemic index.


GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak.
Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.


Case management for high-intensity service users: towards a relational approach to care co-ordination.
This study is based on a formative evaluation of a case management service for high-intensity service users in Northern England. The evaluation had three main purposes: (i) to assess the quality of the organisational infrastructure; (ii) to obtain a better understanding of the key influences that played a role in shaping the development of the service; and (iii) to identify potential changes in practice that may help to improve the quality of service provision. The evaluation was informed by Gittell's relational co-ordination theory, which focuses upon cross-boundary working practices that facilitate task integration. The Assessment of Chronic Illness Care Survey was used to assess the organisational infrastructure and qualitative interviews with front line staff were conducted to explore the key influences that shaped the development of the service. A high level of strategic commitment and political support for integrated working was identified. However, the quality of care co-ordination was variable. The most prominent operational factor that appeared to influence the scope and quality of care co-ordination was the pattern of interaction between the case managers and their co-workers. The co-ordination of patient care was much more effective in integrated co-ordination networks. Key features included clearly defined, task focussed, relational workspaces with interactive forums where case managers could engage with co-workers in discussions about the management of interdependent care activities. In dispersed co-ordination networks with fewer relational workspaces, the case managers struggled to work as effectively. The evaluation concluded that the creation of flexible and efficient task focused relational workspaces that are systemically managed and adequately resourced could help to improve the quality of care co-ordination, particularly in dispersed networks.


Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension.
Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p < 10(-16)). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p < 10(-03)). These results were independent of age, BMI, ethnicity and sex. The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension.


Molecular Communications Pulse-Based Jamming Model for Bacterial Biofilm Suppression.
Studies have recently shown that the bacteria survivability within biofilms is responsible for the emergence of superbugs. The combat of bacterial infections, without enhancing its resistance to antibiotics, includes the use of nanoparticles to quench the quorum sensing of these biofilm-forming bacteria. Several sequential and parallel multi-stage communication processes are involved in the formation of biofilms. In this paper, we use proteomic data from a wet lab experiment to identify the communication channels that are vital to these processes. We also identified the main proteins from each channel and propose the use of jamming signals from synthetically engineered bacteria to suppress the production of those proteins. This biocompatible technique is based on synthetic biology and enables the inhibition of biofilm formation. We analyze the communications performance of the jamming process by evaluating the path loss for a number of conditions that include different engineered bacterial population sizes, distances between the populations, and molecular signal power. Our results show that sufficient molecular pulse-based jamming signals are able to prevent the biofilm formation by creating lossy communications channels (almost -3 dB for certain scenarios). From these results, we define the main design parameters to develop a fully operational bacteria-based jamming system.


Identification of factors required for meristem function in Arabidopsis using a novel next generation sequencing fast forward genetics approach.
Phenotype-driven forward genetic experiments are powerful approaches for linking phenotypes to genomic elements but they still involve a laborious positional cloning process. Although sequencing of complete genomes now becomes available, discriminating causal mutations from the enormous amounts of background variation remains a major challenge. To improve this, we developed a universal two-step approach, named 'fast forward genetics', which combines traditional bulk segregant techniques with targeted genomic enrichment and next-generation sequencing technology As a proof of principle we successfully applied this approach to two Arabidopsis mutants and identified a novel factor required for stem cell activity. We demonstrated that the 'fast forward genetics' procedure efficiently identifies a small number of testable candidate mutations. As the approach is independent of genome size, it can be applied to any model system of interest. Furthermore, we show that experiments can be multiplexed and easily scaled for the identification of multiple individual mutants in a single sequencing run.


Relationship between Fatigue, Sleep Disturbance, and Gestational Stress among Pregnant Women in the Late Stages.
The objective of this study was to investigate the relationship between fatigue, sleep disturbance, and gestational stress in women during late stage of pregnancy. This study was conducted with 113 healthy pregnant women at gestational age greater than 27 weeks who were registered at community health centers and received prenatal care. A structured questionnaire regarding fatigue, sleep disturbance, and gestational stress was used. The data was analyzed using a t-test, an ANOVA, and Pearson correlation coefficients. The subjects with unplanned pregnancies and irregular exercise patterns showed a higher level of fatigue than those with planned pregnancies and regular exercise patterns. Pregnant women with caffeine intake manifested higher levels of gestational stress and sleep disturbance than those without. The levels of sleep disturbance and gestational stress increased as the fatigue levels increased. The fatigue levels increased with increased levels of sleep disturbance. Planned pregnancy, regular exercise patterns, and caffeine intake were related with fatigue, sleep disturbance, and gestational stress in women during late stages of pregnancy. Fatigue, sleep disturbance, and gestational stress had close associations to each other. In the future, such results should guide development of nursing intervention programs for women in late stages of pregnancy.


Endogenous digitalis-like factors: an overview of the history.
The sodium pump is a ubiquitous cell surface enzyme, a Na, K ATPase, which maintains ion gradients between cells and the extracellular fluid (ECF). The extracellular domain of this enzyme contains a highly conserved binding site, a receptor for a plant derived family of compounds, the digitalis glycosides. These compounds inhibit the enzyme and are used in the treatment of congestive heart failure and certain cardiac arrhythmias. The highly conserved nature of this enzyme and its digitalis receptor led to early suggestions that endogenous regulators might exist. Recent examination of this hypothesis emerged from research in two separate areas: the regulation of ECF volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na, K ATPase. These two areas merged with the hypothesis that NH and the vascular Na, K ATPase inhibitor were in fact the same entity, and that it played a causative role in the pathophysiology of certain types of hypertension. The possibility that multiple endogenous digitalis-like factors (EDLFs) exist emerged from efforts to characterize the circulating enzyme inhibitory activity. In this review, the development of this field from its beginnings is traced, the current status of the structure of EDLFs is briefly discussed, and areas for future development are suggested.


Fatal giant pediatric intracranial cavernous angioma.
Cavernous angioma is a benign vascular lesion that may occur in the central nervous system. The symptoms of raised intracranial pressure or consciousness alteration are usually related to acute hemorrhage. A previously healthy four-year-old girl was admitted with sudden loss of consciousness, vomiting and clonic seizures. Her Glasgow coma score (GCS) was 7 at presentation (5 m 1v 1e). Anisocoria and mydriasis were present on the right. Computerized tomography revealed a giant spherical, hyperdense intraaxial left frontoparietal lesion. The findings of surrounding vasogenic edema and compression of the adjacent lateral ventricle were seen on computerized tomography (CT). She was taken to operation and the mass was grossly excised. The GCS remained unchanged. A diagnosis of brain death was made. A cavernous hemangioma was diagnosed with pathologic examination. In conclusion, a cavernous angioma may occasionally follow a rapid and fatal course by causing gross hemorrhage in the pediatric age group. Early recognition by CT or magnetic resonance imaging (MRI) and prompt surgical evacuation are necessary.


Morphologic features of melanophages under in vivo reflectance confocal microscopy.
To determine morphologic features of melanophages under in vivo reflectance confocal microscopy (RCM) and to highlight morphologic features that are important in distinguishing melanophages from melanocytes. Consecutive retrospective study. Referral center for pigmented lesions. The study group retrospectively constituted 20 consecutive patients having biopsy-proven lichen planus-like keratoses that dermoscopically and histopathologically showed many melanophages and that had been imaged under RCM before biopsy. The RCM characteristics of isolated dermal bright cells were scored blinded to dermoscopic features and histopathologic diagnosis. Under RCM, melanophages were significantly smaller than melanocytes (mean [SD] cell diameter, 13.6 [1.6] vs 18.2 [2.9] microm, P = .006). Nuclei (intracellular low-reflectance round-oval structures) were visible in only 16% (29 of 184) of the cells in melanophages vs 57% (28 of 49) of the cells in melanocytes (P < .001). When identified, nuclei were smaller in melanophages than in melanocytes (mean [SD] diameter, 3.2 [1.2] vs 6.4 [0.7] microm, P < .001). Compared with melanocytes, melanophages were significantly more ill defined (76% [140 of 184] vs 18% [9 of 49], P < .001), less round (23% [42 of 184] vs 69% [34 of 49], P < .001), and less dendritic (1% [2 of 184] vs 12% [6 of 49]) (P = .001). Observed differences in morphologic features should enable distinction between melanophages and melanocytes under RCM, thereby improving the accuracy of skin lesion diagnosis using this technique.


Exploring alexithymia, depression, and binge eating in self-reported eating disorders in women.
Binge eating is often a way of life for many women even if the diagnostic criteria for the tentative DSM-IV-TR diagnosis of binge eating disorder is not met. Binge eating was conceptualized as a problem in affect regulation. Affective indices of alexithymia and depression were measure with the Toronto Alexithymia Scale (TAS), the Alexithymia-Provoked Response Questionnaire (APQR), and the Beck Depression Inventory (BDI), respectively. This study was an exploratory study of 65 subjects, 35 of whom self-reported as eating disordered and 30 as non-eating disordered. Of the eating-disordered subjects, 95% scored significantly on the Eating Habits Checklist as binge eaters, 18% as anorexic, and 23% as bulimic. Significant relationships were found between alexithymia and binge eating and depression. A stepwise logistic regression found that both alexithymia and depression discriminated between women with and without binge eating at .001 and .002, respectively. This study found that alexithymia was more highly correlated with binge eating than with either anorexia or bulimia. In addition, a significant history of trauma and health problems for those who reported as binge eaters was reported. Implications for practice are discussed.


Determination of local myocardial electrical activation for activation sequence mapping. A statistical approach.
Electrical activation sequence mapping requires accurate identification of local activation, but because extracellular recordings do not exclusively reflect local events, complex electrograms may be difficult to interpret. In such cases, the assignment of local activation is subject to error that could affect interpretation of the resulting activation maps. The purpose of this investigation was to develop an approach that would provide quantitative indexes of error in the determination of local activation. An electrode array with 64 closely spaced unipolar electrodes was used to record from the left ventricular surface during open heart surgery. Electrograms with multiple deflections were recorded from four patients with scarred myocardium; two other patients with normal myocardial function served as controls. Each of 784 deflections was scored on the basis of three features: evidence for propagation, the configuration of the bipolar signal, and the effect of changing from the chest to an average reference. Local activation was considered probable if evidence for all three features was present and improbable if none of the three features was present. Deflections that were ambiguous with respect to this standard were excluded. Of over 30 test variables analyzed, the three with the greatest power to discriminate signals due to local activation from those due to distant activity were 1) a linear combination of the extracellular potential plus the ratio of the second derivative and the extracellular potential, 2) the second derivative, and 3) the minimum (greatest negative) first derivative. For each of these variables, the threshold value providing the greatest performance was identified by the maximum quality of efficiency, an index of agreement. This statistical approach provides an objective basis for determining local activation and provides a quantitative assessment of error that could enhance interpretation of electrical activation sequence maps.


Implementation strategies to promote community-engaged efforts to counter tobacco marketing at the point of sale.
The US tobacco industry spends $8.2 billion annually on marketing at the point of sale (POS), a practice known to increase tobacco use. Evidence-based policy interventions (EBPIs) are available to reduce exposure to POS marketing, and nationwide, states are funding community-based tobacco control partnerships to promote local enactment of these EBPIs. Little is known, however, about what implementation strategies best support community partnerships' success enacting EBPI. Guided by Kingdon's theory of policy change, Counter Tools provides tools, training, and other implementation strategies to support community partnerships' performance of five core policy change processes: document local problem, formulate policy solutions, engage partners, raise awareness of problems and solutions, and persuade decision makers to enact new policy. We assessed Counter Tools' impact at 1 year on (1) partnership coordinators' self-efficacy, (2) partnerships' performance of core policy change processes, (3) community progress toward EBPI enactment, and (4) salient contextual factors. Counter Tools provided implementation strategies to 30 partnerships. Data on self-efficacy were collected using a pre-post survey. Structured interviews assessed performance of core policy change processes. Data also were collected on progress toward EBPI enactment and contextual factors. Analysis included descriptive and bivariate statistics and content analysis. Following 1-year exposure to implementation strategies, coordinators' self-efficacy increased significantly. Partnerships completed the greatest proportion of activities within the "engage partners" and "document local problem" core processes. Communities made only limited progress toward policy enactment. Findings can inform delivery of implementation strategies and tests of their effects on community-level efforts to enact EBPIs.


[Allergic rhinitis to be diagnosed and treated correctly. Tips for a runny nose].
Two types of allergic rhinitis are differentiated: seasonal rhinitis caused in particular by pollen allergens, and the perennial form caused by such year-round allergens as house dust (mites), moulds and animal hair. The diagnosis is based on a comprehensive history (family/occupation/environment), clinical symptoms, a rhinoscopic examination, and testing for allergens, e.g. conjunctival tests, prick test or nasal provocative test. The treatment of choice is elimination of the allergens as completely as possible. An additional causal therapeutic option is specific immune therapy (SIT) which, however, is contraindicated in the presence of intercurrent infections, use of beta blockers and immunodeficiency. Available medications include mast cell stabilizers, antihistaminic agents and corticosteroids, which are applied in stepped fashion, depending upon severity. In addition, adjuvant surgical measures may improve obstructive symptoms.


Interleukin-12-induced cytotoxicity against syngeneic B cell lymphomas of SJL/J mice.
The B cell lymphomas (RCS) that develop spontaneously in 90% of aging SJL/J mice stimulate syngeneic CD4+ Vbeta16+ Th2 cells to produce cytokines, such as IL-4 and IL-5, which promote lymphoma growth. Although RCS cells express a unique superantigen (vSAg) encoded by an endogenous MMTV (Mtv-29) provirus that also elicits IFN-gamma production from naïve syngeneic lymphoid cells, there is no development of RCS-specific cytotoxicity. However, addition of IL-12 to co-cultures of SJL spleen and irradiated (gamma-)RCS cells resulted in the appearance of effector cells that killed RCS and NK-susceptible target cells. Antibody depletion studies revealed at least two types of RCS/IL-12-induced cytotoxic cells: (1) NK cells (Asialo GM1+) and (2) CD8+ CTL. Despite high titers of IFN-gamma in the SN of co-culture of SJL spleen and gamma-RCS cells, cytotoxicity only developed if IL-12 was also included in the co-cultures. The results of RNAse protection assays and multi-parameter FACS analysis demonstrated an upregulation of IFN-gamma and decrease in IL-4 by activated Th cells in co-cultures with IL-12. These results indicate that inclusion of IL-12 in primary co-cultures of SJL spleen and gamma-RCS cells influences the qualitative nature of the response to favor use of RCS-responsive Th1 rather than Th2 cells to facilitate the production of cytotoxic effector cells. Results of in vivo experiments support this hypothesis, as judged by tumor growth assays and FACS analysis of the tumor cell content of lymphoid tissues. Inhibition of lymphoma growth was observed in mice given gamma-RCS/IL-12-induced effector cells prior to injection of viable RCS cells. These results demonstrate that IL-12 can be used to alter the host immune response leading to induction of cytotoxic effector cells that inhibit the development and/or progressive growth of otherwise resistant B cell lymphomas in SJL/J mice.


Overconfidence among beginners: Is a little learning a dangerous thing?
Across 6 studies we investigated the development of overconfidence among beginners. In 4 of the studies, participants completed multicue probabilistic learning tasks (e.g., learning to diagnose "zombie diseases" from physical symptoms). Although beginners did not start out overconfident in their judgments, they rapidly surged to a "beginner's bubble" of overconfidence. This bubble was traced to exuberant and error-filled theorizing about how to approach the task formed after just a few learning experiences. Later trials challenged and refined those theories, leading to a temporary leveling off of confidence while performance incrementally improved, although confidence began to rise again after this pause. In 2 additional studies we found a real-world echo of this pattern of overconfidence across the life course. Self-ratings of financial literacy surged among young adults, then leveled off among older respondents until late adulthood, where it begins to rise again, with actual financial knowledge all the while rising more slowly, consistently, and incrementally throughout adulthood. Hence, when it comes to overconfident judgment, a little learning does appear to be a dangerous thing. Although beginners start with humble self-perceptions, with just a little experience their confidence races ahead of their actual performance. (PsycINFO Database Record


Are color or high rearing density related to migratory polyphenism in the band-winged grasshopper, Oedaleus asiaticus?
Locusts represent an impressive example of migratory polyphenism, with high densities triggering a switch from a solitarious, shorter dispersal range, and sometimes greenish phenotype to a gregarious and sometimes darker form exhibiting behavioral, morphological and physiological traits associated with long-distance migratory swarms. While such polyphenism has been well documented in Locusta migratoria and Schistocerca gregaria, the extent to which other grasshoppers exhibit this type of migratory polyphenism is unclear. Anecdotally, the Chinese grasshopper, Oedaleus asiaticus, forms migratory swarms comprised mostly of a darker, brown-colored morph, but also exhibits a non-migratory green-colored morph that predominates at low densities. In a population in Inner Mongolia not currently exhibiting migratory swarms, we found that while green and brown O. asiaticus are found concurrently across our sampled range, only brown grasshoppers were found in high densities. Differences between field-collected brown and green forms matched some but not key predictions associated with the hypothesis that the brown form is morphologically and physiologically specialized for gregarious migration. Controlling for body mass, brown forms had more massive thoraxes, abdomens and legs, and higher metabolic rates, but not more flight muscle or lipid stores. Further, the brown and green grasshoppers did not differ in gregarious behavior, and neither would fly in multiple lab and field trials. Lab or field-rearing at high densities for one-to-multiple juvenile instars caused grasshoppers to exhibit some morphological traits predicted to benefit migration (larger wings and a shift in relative mass from abdomen to thorax), but did not change color or induce flight behavior. One hypothesis to explain these data is that a migratory form of O. asiaticus is partially triggered by high field densities, but that existing ecological conditions blocked full expression of such traits (and outbreak swarms). Alternatively, color variation in this species may more tightly linked to other functions in this species such as crypsis or disease resistance, and mechanisms other than late-juvenile rearing density (e.g. genetic variation, maternal effects) may be more critical for promoting variation in color and/or migratory polyphenism.


Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception.
The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca2+ uniporter - MCU, controls mitochondrial Ca2+ entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria. The functional interplay between TRPV1, MCU and NCLX, in controlling the cytosolic and mitochondrial calcium and sodium transients and subsequently the nociceptive excitability, is poorly understood. Here, we used cytosolic and mitochondrial fluorescent calcium and sodium imaging together with electrophysiological recordings of TRPV1-induced currents in HEK293T cells and nociceptor-like dissociated rat dorsal root ganglion neurons, while modulating NCLX or MCU expression using specific small interfering RNA (siNCLX). We show that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. Thus, knocking-down of NCLX triggers down regulation of MCU dependent mitochondrial Ca2+ uptake. This in turn decreases rate and amplitude of TRPV1-mediated cytosolic calcium, which inhibits capsaicin-induced inward current and neuronal firing. TRPV1-mediated currents were fully rescued by intracellular inclusion of the fast calcium chelator BAPTA. Finally, NCLX controls capsaicin-induced cell death, by supporting massive mitochondrial Ca2+ shuttling. Altogether, our results suggest that NCLX, by regulating cytosolic and mitochondrial ionic transients, modulates calcium-dependent desensitization of TRPV1 channels, thereby, controlling nociceptive signaling.


DNA Origami-Mediated Substrate Nanopatterning of Inorganic Structures for Sensing Applications.
Structural DNA nanotechnology provides a viable route for building from the bottom-up using DNA as construction material. The most common DNA nanofabrication technique is called DNA origami, and it allows high-throughput synthesis of accurate and highly versatile structures with nanometer-level precision. Here, it is shown how the spatial information of DNA origami can be transferred to metallic nanostructures by combining the bottom-up DNA origami with the conventionally used top-down lithography approaches. This allows fabrication of billions of tiny nanostructures in one step onto selected substrates. The method is demonstrated using bowtie DNA origami to create metallic bowtie-shaped antenna structures on silicon nitride or sapphire substrates. The method relies on the selective growth of a silicon oxide layer on top of the origami deposition substrate, thus resulting in a patterning mask for following lithographic steps. These nanostructure-equipped surfaces can be further used as molecular sensors (e.g., surface-enhanced Raman spectroscopy (SERS)) and in various other optical applications at the visible wavelength range owing to the small feature sizes (sub-10 nm). The technique can be extended to other materials through methodological modifications; therefore, the resulting optically active surfaces may find use in development of metamaterials and metasurfaces.


System for analysing sickness absenteeism in Poland.
The National System of Sickness Absenteeism Statistics has been functioning in Poland since 1977, as the part of the national health statistics. The system is based on a 15-percent random sample of copies of certificates of temporary incapacity for work issued by all health care units and authorised private medical practitioners. A certificate of temporary incapacity for work is received by every insured employee who is compelled to stop working due to sickness, accident, or due to the necessity to care for a sick member of his/her family. The certificate is required on the first day of sickness. Analyses of disease- and accident-related sickness absenteeism carried out each year in Poland within the statistical system lead to the main conclusions: 1. Diseases of the musculoskeletal and peripheral nervous systems accounting, when combined, for 1/3 of the total sickness absenteeism, are a major health problem of the working population in Poland. During the past five years, incapacity for work caused by these diseases in males increased 2.5 times. 2. Circulatory diseases, and arterial hypertension and ischaemic heart disease in particular (41% and 27% of sickness days, respectively), create an essential health problem among males at productive age, especially, in the 40 and older age group. Absenteeism due to these diseases has increased in males more than two times.


Effects of macromolecular transport and stochastic fluctuations on dynamics of genetic regulatory systems.
To predict the dynamics of genetic regulation, it may be necessary to consider macromolecular transport and stochastic fluctuations in macromolecule numbers. Transport can be diffusive or active, and in some cases a time delay might suffice to model active transport. We characterize major differences in the dynamics of model genetic systems when diffusive transport of mRNA and protein was compared with transport modeled as a time delay. Delays allow for history-dependent, non-Markovian responses to stimuli (i.e., "molecular memory"). Diffusion suppresses oscillations, whereas delays tend to create oscillations. When simulating essential elements of circadian oscillators, we found the delay between transcription and translation necessary for oscillations. Stochastic fluctuations tend to destabilize and thereby mask steady states with few molecules. This computational approach, combined with experiments, should provide a fruitful conceptual framework for investigating the function and dynamic properties of genetic regulatory systems.


Psychometric analysis of the BASC-2 Behavioral and Emotional Screening System (BESS) student form: Results from high school student samples.
The Behavioral and Emotional Screening System (BESS) is a relatively new method for identifying behavior and emotional risk (BER) in children and adolescents. Psychometric evidence regarding this instrument is important for researchers and practitioners considering the use of the BESS for identifying BER in students. Previous psychometric research specifically regarding the BESS Student Form involved the use of samples of elementary and middle school-age children. This study adds to the psychometric evidence for scores on the BESS Student Form by using samples of high school aged students to assess both the factor structure reported by Dowdy, Twyford et al. (2011) and the measurement invariance of the BESS items with regard to ethnicity, English language proficiency, and socioeconomic status. The results indicate that while the proposed 4-factor structure of the BESS Student Form is appropriate, lower than preferred reliabilities for some of the factors indicates that reporting the overall risk T score is more appropriate than reporting factor scores for risk classification purposes. Additionally, the BESS Student Form items did not exhibit measurement bias when comparing across ethnicities, language proficiency classification, or socioeconomic status (via free/reduced lunch classification).


Summary of track D: social science: research, policy and action.
This review summarizes the main issues discussed during Track D, which examined the societal impact of HIV/AIDS, and responses to the epidemic by individuals, families, communities and societies worldwide. Micro- and macrolevel issues addressed included the development, implementation and evaluation of programmes for prevention and care; policy development and implementation; structural issues such as the impact of gender relations, development and migration on the development of the epidemic; and the social and economic impact of HIV/AIDS on affected societies and communities. Presentations provided strong evidence that peer-led, community-based programmes offer particularly effective ways of working, and that participatory research involving affected communities provides useful results for the design and evaluation of programmes and policies. This is the case across settings, issues, populations and countries. Emerging needs include how best to ensure sustainability of national and international responses, how best to scale up successful interventions for wider reach, and how best to work with systematically marginalized, neglected groups and populations. Research priorities include the characterization of the multiple determinants of HIV-related vulnerability, and the evaluation of interventions that take these complex determinants as their starting point. A more coherent and strategic response requires less separation between the different constituencies involved in AIDS work, and the more sustained involvement of people living with HIV/AIDS themselves.


Pharmacokinetics of insulin-like growth factor I in hypopituitarism: correlation with binding proteins.
We investigated the pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) in growth hormone deficiency (GHD). Nine GHD adults [age 25 +/- 3 (SE) yr] received rhIGF-I (60 microgram/kg sc) twice, 10 h apart, and blood was sampled over 24 h. IGF-I and free IGF-I concentrations increased, whereas IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) were unchanged during treatment. There was no correlation between absorption or terminal half-life of IGF-I and IGFBP-3 or ALS, but negative correlations with IGF-I clearance (CL/F) and volume of distribution (V/F). Positive correlations between both IGFBP-3 and ALS and IGF-I maximal concentration (C(max)) and time of C(max) (T(max)) were observed. Compared with normal individuals studied similarly (using 80 microgram/kg), GHD subjects showed a normal absorption half-life, a faster elimination half-life, lower C(max), yet normal T(max) and V/F. In conclusion, GHD is associated with normal absorption and distribution of IGF-I yet faster elimination kinetics. Additionally, IGFBP-3 and ALS concentrations modulate the peak concentrations of IGF-I achieved and correlate reciprocally with its V/F and CL/F, underscoring the critical importance of binding proteins in modulating the bioavailability of IGF-I in vivo in humans.


Surface modified microprojection arrays for the selective extraction of the dengue virus NS1 protein as a marker for disease.
While advances in assay chemistry and detection continue to improve molecular diagnostics technology, blood samples are still collected using the 150-year-old needle/syringe method. Surface modified microprojection arrays have been developed as a novel platform for in vivo, needle-free biomarker capture. These devices are gold coated silicon arrays with >20,000 projections per cm(2), which can be applied to the skin for tunable penetration into the epidermis or dermis. The microprojection array conceptually offers several advantages over the current methods including: minimally invasive sample collection, no need for sample processing and concentration of specific markers at the device surface for sensitive detection. In this study, Microprojection arrays were coated with antibodies to capture an early marker of dengue virus infection, NS1, from the skin of live mice. We also developed a complementary "total IgG" assay which could be used as a positive control for adequate penetration of the projections. Surface modifications designed for selective extraction were tested against standard microtiter plate ELISA. We also investigated the use of Protein G-mediated antibody immobilization in order to orient capture antibodies. While we found that capture efficiency could be improved, the direct EDC-based antibody immobilization resulted in a significantly higher surface density leading to a higher degree of NS1 capture. Using mice intravenously injected with recombinant dengue virus type 2 NS1 as a pseudomodel for dengue infection, NS1 was successfully extracted using microprojection arrays sampling from skin fluid, with a detection limit of 8 μg/mL.


Treatment of idiopathic clubfoot: an historical review.
Idiopathic clubfoot, one of the most common problems in pediatric orthopaedics, is characterized by a complex three-dimensional deformity of the foot. The treatment of clubfoot is controversial and continues to be one of the biggest challenges in pediatric orthopaedics. This controversy is due in part to the difficulty in measuring and evaluating the effectiveness of different treatment methods. We believe the heart of the debate is a lack of understanding of the functional anatomy of the deformity, the biological response of young connective tissue to injury and repair, and their combined effect on the long-term treatment outcomes. The aim of this review is not only to assess the different methods of clubfoot treatment used over the years in light of an evolving understanding of the pathoanatomy of the deformity, but to also clarify factors that allow a safe, logical approach to clubfoot management. Further research will be needed to fully understand the pathogenesis of clubfoot, as well as the long-term results and quality of life for the treated foot.


Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT.
Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies. The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor (NVP-BKM120), a p110α isoform-specific PI3K inhibitor (NVP-BYL719), an mTORC1-specific inhibitor (NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor (NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines. Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor-positive and/or HER2(+) cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2(+) breast cancer models. The PI3K/mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1-2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo. These preclinical data support the findings of the BOLERO 3 trial that shows that targeting of the PI3K/mTOR pathway in combination with trastuzumab is beneficial in trastuzumab-resistant breast cancer.


Using hub technology to facilitate information system integration in a health-care enterprise.
The deployment and maintenance of multiple point-to-point interfaces between a clinical information system, such as a laboratory information system, and other systems within a healthcare enterprise is expensive and time consuming. Moreover, the demand for such interfaces is increasing as hospitals consolidate and clinical laboratories participate in the development of regional laboratory networks and create host-to-host links with laboratory outreach clients. An interface engine, also called a hub, is an evolving technology that could replace multiple point-to-point interfaces from a laboratory information system with a single interface to the hub, preferably HL7 based. The hub then routes and translates laboratory information to other systems within the enterprise. Changes in application systems in an enterprise where a centralized interface engine has been implemented then amount to thorough analysis, an update of the enterprise's data dictionary, purchase of a single new vendor-supported interface, and table-based parameter changes on the hub. Two other features of an interface engine, support for structured query language and information store-and-forward, will facilitate the development of clinical data repositories and provide flexibility when interacting with other host systems. This article describes the advantages and disadvantages of an interface engine and lists some problems not solved by the technology. Finally, early developmental experience with an interface engine at the University of Michigan Medical Center and the benefits of the project on system integration efforts are described, not the least of which has been the enthusiastic adoption of the HL7 standard for all future interface projects.


Considerations for personalized neoantigen vaccination in Malignant glioma.
Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued advances in immunotherapy for other cancer types, however, there remain no FDA approved immunotherapies for cancers such as glioblastoma. OF the many approaches being explored, cancer vaccine programs are undergoing a renaissance due to the technological advances and personalized nature of their contemporary design. Neoantigen vaccines are a form of immunotherapy involving the use of DNA, mRNA, and proteins derived from non-synonymous mutations identified in patient tumor tissue samples to stimulate tumor-specific T-cell reactivity leading to enhance tumor targeting. In the last several years, the study of neoantigens as a therapeutic target has increased, with the routine workflow implementation of comprehensive next generation sequencing and in silico peptide binding prediction algorithms. Several neoantigen vaccine platforms are being evaluated in clinical trials for malignancies including melanoma, pancreatic cancer, breast cancer, lung cancer, and glioblastoma, among others. In this review, we will review the concept of neoantigen discovery using cancer immunogenomics approaches in glioblastoma and explore the disease-specific issues being addressed in the design of effective personalized cancer vaccine strategies.


Delayed activation of tuberoinfundibular dopamine neurons and suppression of prolactin secretion in the rat after morphine administration.
The effect of morphine administration on the subsequent stimulation of prolactin (PRL) secretion and the release of dopamine from tuberoinfundibular neurons was examined in this study. The administration of morphine (15 mg/kg s.c.) resulted 4 hr later in suppressed serum PRL concentrations. In addition, the increase in serum PRL concentrations induced by restraint stress was attenuated greatly in rats treated 4 hr earlier with morphine. The morphine-induced attenuation of the PRL response to restraint stress was time-dependent and dose-related. The suppressive effect of morphine on PRL secretion was observed 3 to 6 hr after its administration and at doses of 10 to 20 mg/kg. A single injection of morphine also resulted 4 hr later in an attenuation of the PRL response to a second injection of morphine (7.5 mg/kg); however, the increase in serum PRL concentration produced by alpha-methyltyrosine (250 mg/kg) was unaltered by prior morphine administration. The suppressive effect of morphine on PRL secretion was not observed in rats treated with the opiate antagonist naloxone (2.5 mg/kg). Associated with the delayed suppressive effect of morphine on serum PRL concentrations was a delayed increase in the concentration of dopamine in hypophysial portal plasma and an increase in the turnover of dopamine in the median eminence. The morphine-induced stimulation of the release of dopamine into hypophyseal portal blood was attenuated significantly in animals treated with naltrexone (1 mg/kg). It is concluded that morphine exerts a biphasic effect on both the secretion of PRL and the release of dopamine from tuberoinfundibular neurons.(ABSTRACT TRUNCATED AT 250 WORDS)


Association Between Chronic Back Pain and Protective Behaviors is Subjective and Context Dependent.
Chronic lower back (CLB) pain limits patients' day-to-day activities, increases their missed days of work, and causes emotional distress. Developing adequate and individual-tailored treatment for CLB patients requires a better understanding of pain and protective behaviors, and how these behaviors are modulated or altered by context and subjectivity. In this work, we conducted experiments to investigate 1) the relationship between pain and protective behaviors in patients with CLB pain, 2) whether individual differences and context are relevant factors in the relationship, and 3) the impact of this relationship and its factors on the performance of current automated models for pain and protective behavior perception. Our results show 1) significant association (p - value < 0.05) between pain and protective behaviors in patients with CLB pain and 2) subjectivity and context are influential factors in this association. Further, our results show that considering this association along with its factors significantly (p-value < 0.05) improves the performance of automated pain and protective behaviors perception. These findings highlight the role of this association on pain and protective behaviors perception and raise several questions about the robustness of existing automated models that do not take this association into account.


Identification of spectral forms of protochlorophyllide in the region 670-730 nm.
Dark-grown leaves of three different species, maize, wheat, pea and a pea mutant (lip1) have been used to study protochlorophyllide (Pchlide) spectral forms. As a comparison also pea epicotyls were used. Different native forms of Pchlide were identified using the variation in the spectral properties of the plant material and the second derivatives of the 77 K fluorescence excitation and emission spectra. The spectral forms were further characterised by Gaussian deconvolution. In addition to short-wavelength and long-wavelength forms the area between 660 and 730 nm was shown to contain, together with some vibrational bands, five far-red Pchlide forms. They had pairs of excitation and emission peaks at 658 and 666 nm, 668 and 680 nm, 677 and 690 nm, 686 and 698 as well as 696 and 728 nm, respectively. The presence of several far-red Pchlide forms in dark-grown leaves gave evidence for additional aggregated states of Pchlide under native conditions.


An analysis of the length of hospital stay after acetaminophen overdose.
Acetaminophen is one of the most commonly encountered medications in self-poisoning, with a high rate of morbidity. The prevalence and characteristics of acetaminophen intoxication associated with long hospital stay in patients are not well defined. This study aims to identify the clinical and demographic factors associated with the length of in-hospital stay (LOS), and to evaluate the effect of early treatment of acetaminophen overdose patients (≤8 hours) by intravenous N-acetylcysteine (IV-NAC) on hospital stay. This is a retrospective cohort study of hospital admissions for acetaminophen overdose conducted over a period of 5 years from 1 January 2004 to 31 December 2008. Patients were divided into two groups: LS group patients had a long hospital stay (> median hours stay in hospital) and SS group patients had a short hospital stay (≤ median hours stay in hospital). Variables were abstracted from medical records for comparison between the two groups. A total of 20 variables were identified for comparison. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. Of the 305 patients, 11 factors were identified in the univariate analysis as associated with LS. Three independent factors were found to be significant predictors of LS in the multivariate analysis. The factors associated with LS were seen among patients with a history of abdominal pain after ingestion of acetaminophen (p = 0.04), who were on IV-NAC administration (p < 0.001) and had an acutely depressed mood (p = 0.003). Late time to NAC infusion of more than 8 hours was associated with LS rather than SS (96 patients [57%] and 6 [24%], respectively; p = 0.003). Patients with long hospital stay have different clinical characteristics compared to patients with short hospital stay. We identified time to IV-NAC administration is a potentially modifiable factor that may lead to prolonged hospital stay. When risk assessment indicates that NAC is required, it is highly recommended that NAC be started in the first hours of admission to reduce the LOS.


[Update on the treatment of RASopathies].
The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes. To review the use of therapeutic strategies with mechanisms that have a selective action on RASopathies. The fact that the RAS pathway is involved in a third of all neoplasms has led to the development and study of different drugs at this level. Some of these pharmaceutical agents have been tested in RASopathies, mainly in neurofibromatosis type 1. Here we analyse the use of different antitarget treatments: drugs that act on the membrane receptors, such as tyrosine kinase inhibitors, in the mTOR pathway or MEK inhibitors. These latter have shown potential benefits in recent studies conducted on different RASopathies. Today, thanks to the results from the first studies conducted with MEK inhibitor based mainly on animal models, a number of promising clinical trials are being carried out.


The partial volume effect in the quantification of 1H magnetic resonance spectroscopy in Alzheimer's disease and aging.
1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons.


Inhibiting the growth of pancreatic adenocarcinoma in vitro and in vivo through targeted treatment with designer gold nanotherapeutics.
Pancreatic cancer is one of the deadliest of all human malignancies with limited options for therapy. Here, we report the development of an optimized targeted drug delivery system to inhibit advanced stage pancreatic tumor growth in an orthotopic mouse model. METHODPRINCIPAL FINDINGS: Targeting specificity in vitro was confirmed by preincubation of the pancreatic cancer cells with C225 as well as Nitrobenzylthioinosine (NBMPR - nucleoside transporter (NT) inhibitor). Upon nanoconjugation functional activity of gemcitabine was retained as tested using a thymidine incorporation assay. Significant stability of the nanoconjugates was maintained, with only 12% release of gemcitabine over a 24-hour period in mouse plasma. Finally, an in vivo study demonstrated the inhibition of tumor growth through targeted delivery of a low dose of gemcitabine in an orthotopic model of pancreatic cancer, mimicking an advanced stage of the disease. We demonstrated in this study that the gold nanoparticle-based therapeutic containing gemcitabine inhibited tumor growth in an advanced stage of the disease in an orthotopic model of pancreatic cancer. Future work would focus on understanding the pharmacokinetics and combining active targeting with passive targeting to further improve the therapeutic efficacy and increase survival.


Swedish norms for word fluency tests: FAS, animals and verbs.
Verbal fluency tests are useful measures of acquired language impairment and cognitive decline of various etiologies. The aim of this study was to provide normative data for the Swedish population on the three verbal fluency tests, FAS, Animals and Verbs. A group of 165 healthy participants ranging from 16 to 89 years of age were assessed with the verbal fluency tests and tests of level of intellectual functioning. The sample was stratified by education, age and gender. Level of education had a substantial influence on the performance on verbal fluency, most clearly so in FAS and Verbs. Intellectual level had a positive and significant correlation with all measures of word fluency. Moreover, there was an interaction between age and gender such that women aged between 30 and 64 years outperformed elderly men on FAS and Verbs. Guidelines for instructions and scoring in Swedish are given in the article.


Casualty collection in mass-casualty incidents: a better method for finding proverbial needles in a haystack.
Mass-casualty incidents (MCIs) are on the rise. The ability to locate, identify, and triage patients quickly and efficiently results in better patient outcomes. Poor lighting due to time of day, inclement weather, and power outages can make locating patients difficult. Efficient methods of locating patients allow for quicker transport to definitive care. The objective of this study was to evaluate the methods currently used in mass-casualty collection, and to determine whether the use of the Simple Triage and Rapid Treatment (START) triage tag system can be improved by using easily discernable tags (glow sticks) in conjunction with the standard triage tags. Numerous drills were performed utilizing the START triage method. In Trial A, patients were identified with the triage tags only. In Trial B, patients were identified using triage tags and glow sticks. Four rounds of triage drills were performed in low ambient light for each Trial, and the differences in casualty collection times were compared. Casualty relocation and collection times were considerably shorter in the trials that utilized both the glow sticks and triage tags. An average of 2.58 minutes (31.75%) were saved during the casualty collections. In addition, fewer patient errors occurred during the trials in which the glow sticks were used. Between the four rounds, an average of four patient errors occurred during the trials that utilized the triage tags. However, there was an average of only one patient error for the drills when participants utilized both the triage tags and the glow sticks. The use of the highly visible glow sticks, in conjunction with the START triage tags, allowed for more rapid and accurate casualty collection in suboptimal lighting. The use of the glow sticks made it easier to relocate previously triaged patients and arrange for expeditious transport to definitive care. In addition, the glow sticks reduced the number of patient errors. Most importantly, there was a significant reduction in the number of patients that initially were triaged via the START method, but were overlooked during casualty collection and transport.


The ycf 9 (orf 62) gene in the plant chloroplast genome encodes a hydrophobic protein of stromal thylakoid membranes.
There are still some open reading frames, orfs, with unknown function in the higher plant chloroplast genome. Of these conserved orfs, designated as ycfs (hypothetical chloroplast open reading frames), one is ycf 9 (orf 62) in the transcription unit with the psbC and psbD genes. The aim of this work was to investigate the function of ycf 9 by insertional inactivation of the gene with a selectable marker cassette, consisting of the aadA coding region connected to the trc promoter and rrnB terminator. This cassette was inserted 19 bp downstream from the start of the coding region of the tobacco ycf 9 gene. Two DNA constructs with the aadA cassette in opposite orientations were precipitated on 1 micron gold particles and delivered into leaves of Nicotiana tabacum, cultivar Samsun, by the biolistic method. Spectinomycin-resistant plants regenerated following bombardment with only the construct containing the aadA gene in the opposite orientation as ycf 9. In spite of several subsequent regeneration cycles on spectinomycin, the transplastomic plants did not reach homoplasmicity. This suggests that the ycf 9 gene product is essential for chloroplast function. Using a polyclonal antibody raised against the inner part of the gene product, the polypeptide was localized in the stromal thylakoid membranes of chloroplasts.